COMPANY NOTICE OF FILING FOR TETRACONAZOLE NEW USES

PESTICIDE PETITION EPA Registration Division contact: Sidney Jackson, (703) 305-7610

Interregional Research Project Number 4 Pesticide Petition Number 0E7735 EPA has received a pesticide petition (PP 0E7735) from the Interregional Research Project Number 4 (IR-4), 500 College Road East, Suite 201W, Princeton, NJ 08540 proposing, pursuant to section 408(d) of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a(d), to amend 40 CFR part 180. 557 by establishing a tolerance for residues of tetraconazole in or on the raw agricultural commodities small fruit vine climbing, except fuzzy kiwifruit subgroup 13 -07F at 0.2 0 parts per million (ppm) and low growing berry subgroup 13 -07G at 0.25 ppm. Additionally, the petition proposes to delete the existing tolerance for grape at 0.20 ppm since grape is included in the proposed subgroup 13

- 07F. The EPA has determined that the petition contains data or information regarding the elements set forth in section 408 (d) (2) of FDDCA; however, EPA has not fully evaluated the sufficiency of the submitted data at this time or whether the data supports granting of the petition. Additional data may be needed before EPA rules on the petition. A. Residue Chemistry
1. Plant metabolism. T he metabolism of tetraconazole is adequately understood for the purposes of establishing the proposed tolerances. T etraconazole metabolites include 1,2,4-triazole, and two conjugates, triazolylalanine and triazolyl acetic acid, which are common to most of the triazole fungicides. B ased on the available metabolism and toxicology data, parent tetraconazole is proposed to be considered as the residue of concern in plant and animal matrices. Tolerances have previously been approved for many crop and animal matrices. 2. Analytical method. Adequate enforcement methodology (capillary gas chromatography with electron capture detector (GC/ECD)) is available to enforce the tolerance expression. T he method may be requested from: Chief, Analytical Chemistry Branch, Environmental Science center, 701 Mapes Rd., Ft. Meade, MD 20755-5350. 3. Magnitude of residues. For grape group 13 -07F, a total of twelve (12) residue trials were conducted to evaluate the magnitude of the residues of tetraconazole following two applications of METTLE 125ME at 0.04 lbs of active2

ingredient (ai) per acre (a) with treatments 14 days apart and harvest at 14 days after the last application. The grape fruit raw agricultural commodity (RAC) mean was 0.030 ppm with a minimum residue level of 0.005 ppm and a maximum residue level of 0.091 ppm. B oth of the two processed fractions grape juice and raisins did not concentrate having residue levels less than their corresponding grape fruit (RAC). A tolerance has previously been established on grape at 0.20 ppm. For strawberry group 13 -07G, atotal of ten (10) residue trials were conducted to evaluate the magnitude of the residues of tetraconazole following two applications of METTLE 125ME at 0.05 lbs of active ingredient (ai) per acre (a) with treatments 14 days apart and harvest at 0 days after the last application. The strawberry fruit raw agricultural commodity (RAC) mean was 0.0787 ppm with a minimum residue level of less than 0.005 ppm and a maximum residue level of 0.21 1 ppm. No processing studies are required. B. Toxicological Profile 1. Acute toxicity. For formulated product; Acute oral lethal dose (LD 50) = >5000 (combined) milligrams/kilogram (mg/kg) (toxicity category III); acute dermal LD 50 < 2,000 mg/kg (toxicity category III); acute inhalation lethal concentration (LC 50) = 3.17 mg/liter (toxicity category IV); primary eye irritation - clear by 72 hours - Minimal irritant (toxicity category III); primary skin irritation

– not an irritant (toxicity category IV); and dermal sensitization

– negative

– not a sensitizer. 2. Genotoxicty. Numerous mutagenicity studies were conducted with tetraconazole and no genotoxic effects were reported

. 3. Reproductive and developmental toxicity. A two-generation reproduction study was conducted in rats at dietary concentrations of 0, 10, 70 or 490 ppm. The LOAEL for parental toxicity = 70 ppm, equivalent to 4.9/5.9 (male/female) mg/kg/day based on increased mortality in P generation females. The NOAEL = 10 ppm, equivalent to 0.7/0.8 (M/F) mg/kg/day. The LOAEL for off spring toxicity = 490 ppm (40.6 mg/kg/day from the P generation female intake) based on decreased litter weight and mean p up weight in litters of all generations before weaning and increased relative liver weights at weaning in both sexes of all litters. The NOAEL = 70 ppm (5.9 mg/kg/day). The LOAEL for reproductive toxicity = 70 ppm, equivalent to 4.9/5.9 (M/F) mg/kg/day bas ed on increased mean gestation duration in P generation parental females and related evidence of compound toxicity in the parturition process. The NOAEL was 10 ppm (0.7 mg/kg/day for males and 0.8 for females). A developmental toxicity study was conducted using rats gavaged with doses of 0, 5, 22.5, and 100 mg/kg/day from days 2 through 15 of gestation. The maternal toxicity LOAEL is 100 mg/kg/day based on decreased body weight gain, and food consumption and increased liver and kidney weights. The maternal toxicity NOAEL is 22.5 mg/kg/day. Developmental toxicity was noted at 100 mg/kg/day and consisted of an increased incidence of small fetuses, and supernumerary ribs. The LOAEL and NOAEL for developmental toxicity were 100 and 22.5 mg/kg/day, respectively.3

A developmental toxicity study was conducted using rabbits gavaged with doses of 0, 7.5, 15, or 30 mg/kg/day. The maternal toxicity NOAEL = 13 mg/kg/day and LOAEL = 30 mg/kg/day, based upon decreased body weight gain. The developmental toxicity NOAEL = 30 mg/kg/day and the LOAEL was not established. 4. Subchronic toxicity. Ninety-day feeding studies were conducted in rats and mice. The rat study was conduced at dietary concentrations of 0, 10, 60, or 360 ppm. The NOAEL = 4.1/5.5 (M/F) mg/kg/day. The LOAEL = 23.9/28.7 (M/F) mg/kg/day, based on single liver cell degeneration in males, and increased SGPT and SGOT, decreased BUN levels, increased absolute and relative liver weights and presence of hepatocellular single cell necrosis in females. The mouse study was conducted at dietary concentrations of 0, 5, 25, 125, or 625 ppm. The NOAEL = 4 (M/F) mg/kg/day. The LOAEL = 16/20 (M/F) mg/kg/day, based on single liver cell degeneration in males, and increased SGPT and SGOT, decreased BUN levels, increased absolute and relative liver weights and presence of hepatocellular single cell necrosis in females.

5. Chronic toxicity. A two year combined chronic toxicity/carcinogenicity study was conducted in rats at dietary concentrations of 0, 10, 80, 640 or 1280 ppm. T he NOAEL = 3.4/4.4 (M/F) mg/kg/day. The LOAEL = 27.7/39.4 (M/F) mg/kg/day, based upon histopathology of the bone (osseous hypertrophy of the cranium/parietal bone), pale and thickened incisors, and decreased absolute and relative adrenal and pituitary weights in males; decreased body weight (at terminal sacrifice) in females. No treatment-related increases in tumor incidence were observed. A 52 -week chronic toxicity study was conducted in dogs at dietary concentrations of 0, 22.5, 90 or 360 ppm. The NOAEL = 0.73/0.82 (M/F) mg/kg/day. The LOAEL = 27.7/39.4 (M/F) mg/kg/day, based upon increased absolute and relative kidney weights and histopathological changes in the male kidney.

Carcinogenicity. An 80 week mouse oncogenicity study was conducted at dietary concentrations of 0, 10, 90, 800, or 1250 ppm. T he NOAEL = 1.4/1.5 (M/F) mg/kg/day. T he LOAEL = 12/14.5 (M/F) mg/kg/day, based upon increased liver weights and hepatocellular vacuolation in both sexes and increased kidney weights in males. T reatment-related increased incidences of combined benign and malignant liver tumors in both sexes were observed.

6. Animal metabolism. The nature of tetraconazole residues is adequately understood. T etraconazole is extensively metabolized very quickly and eliminated from the body by fecal and urinary routes.

7. Metabolite toxicology

. 1,2 -4 -Triazole is the major metabolite identified in urine and feces with minor amounts of triazole acid and alcohol. The most conservative toxicology endpoint for 1,2,4-triazole is 15 mg/kg/day, based on4

body weight decreases in male rats in the reproductive study. 8. Endocrine disruption

. Tetraconazole did not have effects on endocrine organs or tissues, nor were there any indications of effects on fetal development in either rats or rabbits, or on reproductive performance in rats. Therefore, at doses likely to be encountered, tetraconazole in not likely to be an endocrine disruptor. C. Aggregate Exposure 1. Dietary exposure. (food and drinking water combined) : a. Acute risk: Using 100% crop treated, all existing RAC tolerances plus the presently proposed Small fruit vine climbing subgroup 13 -07F and Low growing berry subgroup 13 -07G RAC tolerance for residue exposure assumptions; the acute dietary exposure from food and water to tetraconazole will occupy < 1.0% of the aPAD for the population group (females 13 to 49 years old) receiving the greatest exposure. No acute toxicity endpoint was identified for the remaining population subgroups. b. Chronic risk: Using 100% crop treated for all food commodities, incorporated empirical processing factors, average field trial residues for all crops, and average residues in meat and meat by-products derived from feeding studies; the exposure to tetraconazole from food and water will utilize 7.7 % of the cPAD for the population group all infants < 1 year old (the most sensitive subpopulation). c. Cancer risk: Using projected percent crop treated estimates for all crops, empirical processing factors plus average field trial residues for all crops, and average residues in meat and meat by-products derived from feeding studies; the estimated cancer risk for the proposed use of tetraconazole on small fruit vine climbing subgroup 13 -07F, low growing berry subgroup 13 -07G, peanuts, pecans, soybeans, sugar beet and water is 3x10 -6

. This aggregate risk is the sum of the risk from food and water and falls within the Agency 's acceptable risk standard for cancer. i. Food. As discussed above ii. Drinking water

. As discussed above. 2. Non

-dietary exposure

. Tetraconazole is currently not registered for use on any residential non-food site. Therefore, residential exposure to tetraconazole residues will be through dietary exposure only. D. Cumulative Ef

fects EPA has not made a common mechanism of toxicity finding as to tetraconazole and any other substance. However, the Agency does have concern about potential toxicity to 1,2,4-triazole and two conjugates, triazolylalanine and triazolyl acetic acid. To support the extension of existing parent triazole-derivative fungicide tolerances, EPA conduced an interim human health assessment for5

aggregate exposure to 1,2,4-triazole. B ased on this assessment EPA concluded that for all exposure durations and p opulation subgroups, aggregate exposures to 1,2,4- triazole are not expected to exceed its level of concern. E. Safety Determination 1. U.S. population. Based on the exposure assumptions described above and on the completeness of the toxicology datab ase, it can be concluded that total aggregate exposure from food and water to the U.S. population and all evaluated population subgroups from tetraconazole exposure from all proposed uses will be below 100% of the RfDs. E PA generally has no concerns for estimated exposures below 100% of the RfD, since the RfD represents the level at or below which daily aggregate exposure will not pose an appreciable risk to human health. Thus, ISAGRO believes it can be concluded that there is reasonable certainty that no harm will result from aggregate exposure to tetraconazole residues for the registered and proposed uses on grape

. 2. Infants and children

. In assessing the potential for additional sensitivity of infants and children to residues of tetraconazole, the data from developmental toxicity studies in both the rat and rabbit and a two generation reproduction study in rats have been considered. These toxicity studies indicate the offspring are not mo re sensitive and all developmental and reproductive effects were secondary to severe maternal toxicity. Thus, ISAGRO believes that infants and children are protected and that an additional uncertainty factor for infants and children is not warranted

. F. International Tolerances

Maximum residue levels (MRL) have been established for tetraconazole in the following countries (in ppm): Belgium : sugar beet root, 0.05; wheat grain, 0.05; wheat straw, 2.0. Brazil : apple, 0.4; banana, 0.2; coffee, 0.08; grape, 0.3; mango, 0.1; soybean, 0.1. France : apple, 0.2; barley grain, 0.02; grape, 0.2; wine, 0.01; sugar beet root, 0.05; wheat grain, 0.02. Italy : apple, 0.5; artichoke, 0.2; barley grain, 0.1; courgette, 0.2; cucumber, 0.2; grape, 0.5; melon, 0.05; peach, 0.2; pear, 0.2; pepper, 0.2; tomato, 0.2, watermelon, 0 .05; wheat grain, 0.05 Portugal : apple, 0.3; grape, 0.2; melon, 0.1; peach, 0.2; pear, 0.3; strawberry, 0.2; sugar beet root, 0.05. Spain : apple, 0.2; artichoke, 0.05; cucurbit fruit & edible peel, 0.2; nectarine, 0.2; peach, 0.2; pear, 0.2; sugar beet leaves, 0.3; sugar beet root; 0.05; tomato, 0.1. United Kingdom : barley grain, 0.2; barley straw, 10; oat grain, 0.1; oat straw, 2; wheat grain, 0.05; wheat straw, 5. Czech Republic : apple, 0.5; grape, 0.05 Hungary : apple, 0.2; grape, 0.5; sugar beet root & leaves, 0.5; sugar beet root, 0.1; wheat grain, 0.05; wheat straw, 3.6

Poland : apple, 0.5; cereal grain, 0.05; cereal straw, 3; cucumber edible peel, 0.2. Japan : wheat, 0.05; barley; 0.2 other cereal grain, 0.1; sugar beet, 0.5; artichoke, 0.2; tomato, 1; cucumber, 0.5; pumpkin (including squash), 1; oriental cucurbitaceous vegetables, 0.2; apple, 0.5, Japanese pear, 0.5, pear, 0.5 quince, 0.5 peach, 0.3, nectarine, 0.2; apricot, 0.2; Japanese plum (including prune); 0.2; cherry, 0.2; strawberry, 2; watermelon, 0.2, melon, 0.2; makuwauri, 0.2; grape, 0.5; tea, 20. No CODEX maximum residue levels (MRL) have been established for residues of tetraconazole on any crops at this time

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